The vast majority of esophageal cancers will develop metastatic disease eventually. Our preliminary data suggest that certain genetic polymorphisms in key pathways may affect survival or prognosis in esophageal and other cancers. Currently, relatively uniform treatment regimens are applied to all patients. A better understanding of the association between germline polymorphisms and prognosis may lead to better treatment strategies and improved outcomes. The proposed study will expand an existing cohort of over 300 esophageal cancer patients established by the Pl's team from 1999-2003 and recruited originally for a pilot case-control study, with the goal of recruiting a total cohort of over 500 patients. Each patient will have a minimum of 3 years of follow-up (and up to 8 years) by the end of the proposed study period. Our overarching aim is to evaluate the roles of genetic polymorphisms in various pathways and their association with esophageal cancer outcomes. The proposed pathways include DNA repair (e.g. ERCC1 ), matrix metalloproteinases, and cell cycle dysregulation (e.g. p53). In addition, polymorphisms of genes involved in the xenobiotic metabolism of commonly-used chemotherapy agents will be assessed, including glutatione stransferases (metabolism of platinum agents), thymidylate synthase (5-fluorouracil), CYP3A5 (taxanes), and UGT1A1 (irinotecan). Outcomes of interest will include disease-free or progression-free survival, and overall survival. To evaluate polymorphisms in linkage disequilibrium, novel in silico haplotyping techniques will be applied. Where feasible, polymorphisms will be correlated with potential biomarkers, such as protein over-expression by immunohistochemical staining. The proposed studies will take advantage of a well-established and well-characterized cohort, an associated extensive pre-treatment tissue bank, and a comprehensive set of preliminary and feasibility results. Furthermore, the proposed studies address directly a prioritized research area identified by the NCI Stomach and Esophageal Cancers Progress Review Group (Year 2002).